1. Field of the Invention
The present invention relates to an MRI contrast medium and, more particularly, to an MRI contrast medium using fluorine as a detectable nucleus.
2. Description of the Related Art
Magnetic resonance imaging (to be referred to as MRI hereinafter) is one of imaging diagnoses, like X-ray imaging, ultrasonic imaging, and nuclear medicine imaging. These imaging diagnoses can visually image pathological changes of living bodies. The imaging diagnoses are, therefore, very excellent means for making accurate diagnoses of diseases and are already used extensively. Among other imaging diagnoses, MRI is a promising imaging diagnosis which has been rapidly spread and developed in recent years.
MRI which is currently being employed in clinical examinations uses .sup.1 H as a detectable nucleus. A measurement target in such MRI is primarily water molecules which exist in a large amount in a living tissue. The principle of this .sup.1 H-MRI is as follows.
The relaxation time, the .sup.1 H density, the .sup.1 H chemical shift, and the like of .sup.1 H constituting a water molecule change depending on an environment in which the water molecule is present. In particular, water molecules present in different tissues of a living body can be distinguished from each other by the difference in relaxation time of .sup.1 H between the water molecules. Therefore, by measuring the relaxation time of .sup.1 H for many water molecules distributed in a living body and imaging the differences in relaxation time between these water molecules, various tissues of the living body can be imaged. Likewise, it is also possible to distinguish a water molecule in a pathologically abnormal tissue from a water molecule in a normal tissue in accordance with the difference in relaxation time of .sup.1 H between these water molecules, and so the pathologically abnormal tissue shows an MRI image different from that of the normal tissue. Therefore, pathological abnormalities can be diagnosed on the basis of MRI images.
Recently, on the other hand, MRI diagnoses using nuclides other than .sup.1 H as detectable nuclei are also being attempted. Examples of the nuclide other than .sup.1 H, which are NMR-spectroscopically detectable, are .sup.19 F, .sup.23 Na, .sup.31 P, and .sup.13 C. When the relative sensitivity and the isotope abundance are taken into account, however, nuclides practically applicable to the MRI diagnoses are .sup.19 F and .sup.31 P. These two nuclides have already been researched for clinical applications. An example of the applications examined is MRS (magnetic resonance spectroscopy) using .sup.31 P as a detectable nucleus to observe the distribution of ATP, ADP, creatine phosphate, inorganic phosphoric acid, and the like in a living body and use the observation result in diagnoses. Since, however, the sensitivity of .sup.31 P is low, 6% that of .sup.1 H, .sup.31 P has its measurement limit, and this makes imaging using .sup.31 P difficult. Therefore, clinical applications of .sup.31 P are also limited.
.sup.19 F, in contrast, has the following characteristics and hence is considered as a nuclide with the highest possibility of being applied to clinical examinations.
(1) .sup.19 F has a high sensitivity, 83% that of .sup.1 H. PA1 (2) Since the resonance frequency of .sup.19 F is close to that of .sup.1 H, measurements can be performed by using an MRI apparatus for .sup.1 H. PA1 (3) .sup.19 F is an inexpensive element with a natural abundance of 100%. PA1 (4) .sup.19 F does not exist in any living tissues but teeth. This makes it possible to perform imaging diagnoses using .sup.19 F as a tracer by using a fluorine-containing compound as a contrast medium. PA1 (5) It is also possible to obtain functional information, such as the biochemical environment and the metabolic state of a living tissue, from a change in biochemical the chemical shift of .sup.19 F. This purpose may be accomplished by using a contrast medium compound containing .sup.19 F, the chemical structure of which changes in accordance with changes in the biochemical environment and metabolic state of a living body, and which consequently changes the chemical environment surrounding .sup.19 F. PA1 (a) Attempts to image blood vessels or organs by administering, as a contrast medium, perfluorocarbon which has been used for artificial blood [Investigative Radiology, 20, 504-509 (1985); Investigative Radiology, 23, S298-S301(1988); Journal of Computer Assisted Tomography, 9(1), 8-5 (1985)]. PA1 (b) Imaging of the difference between oxygen concentrations in a living body as contrast by using perfluorotripropylamine as a contrast medium [Magnetic Resonance Imaging, 5, 279-285 (1987)]. PA1 (c) Imaging of the brains of rats by using well-known 2-fluoro-2-deoxy-D-glucose as a contrast medium in PET (Positron Emission Tomography) [Magnetic Resonance Imaging. 6, 633-635 (1988)]. PA1 (d) Imaging using 5-fluorouracil which is a known anticancer agent [NMR in Biomedicine, (No. 3), 113-120 (1988)]. PA1 (e) A method of imaging the pH distribution in a living tissue as the difference in the chemical shift of .sup.19 F by using a fluorine-substituted benzene derivative [U.S. Pat. No. No. 5,130,119]. PA1 (f) A method of specifically imaging a tissue, such as a cancer lesion, by using an antibody modified with 100 or more fluorine atoms [Jpn. Pat. Appln. KOKAI Publication No. 63 135337]. PA1 z: the ionic valence of Me, a positive integer (preferably 2 or 3) PA1 A: which may be the same or different and each represents a group selected from the group consisting of straight chain or branched chain alkylen groups having 1 to 6 carbon atoms, --(CH.sub.2).sub.1 --O--(CH.sub.2).sub.1 --, and --(CH.sub.2).sub.1 --CO--(CH.sub.2).sub.1 --, wherein 1 is an integer from 1 to 6 PA1 m: an integer from 1 to 6 PA1 X: which may be the same or different and each represents a group selected from the group consisting of --COOZ, --PO.sub.3 HZ, --CONHW, and --OH wherein Z and W are; PA1 n: an integer from 1 to 6 PA1 Y: when n=1, Y is R, wherein R is a substituent which has not less than one fluorine atom and may contain X defined above, and when n=2 or 3, at least one Y is R defined above and each of remaining Y or Ys are --CH.sub.2 X, a lower alkyl group, or a hydrogen atom. PA1 (1) Having specificity for a target tissue and not having cross reactivity for other tissues. In this respect, a monoclonal antibody is particularly desirable. PA1 (2) Acting on an antigen present at a high concentration in a living body and having a high affinity for that antigen. PA1 (3) Acting on an antigen which exists only in a tissue, such as a cell membrane, and is not freed into blood. PA1 z: the ionic valence of Me, a positive integer (preferably 2 or 3) PA1 A: which may be the same or different and each represents a group selected from the group consisting of straight chain or branched chain alkylen groups having 1 to 6 carbon atoms, --(CH.sub.2).sub.1 --O--(CH.sub.2).sub.1 --, and --(CH.sub.2).sub.1 --CO--(CH.sub.2).sub.1 --, wherein 1 is an integer from 1 to 6 PA1 m: an integer from 1 to 6 PA1 X: which may be the same or different and each represents a group selected from the group consisting of --COOZ, --PO.sub.3 HZ, --CONHW, and --OH wherein Z and W are; PA1 n: an integer from 1 to 6 PA1 Y: when n=1, Y is R, wherein R is a substituent which has not less than one fluorine atom and may contain X defined above, and when n=2 or 3, at least one Y is R defined above and each of remaining Ys is --CH.sub.2 X, a lower alkyl group, or a hydrogen atom. PA1 --R.sup.1 F; PA1 --R.sup.2 --Ar.sub.F, --R.sub.2 --.PHI.--R.sub.2 --Ar.sub.F ; PA1 --SO.sub.2 --R.sub.1F, --SO.sub.2 --R.sub.2 --R.sub.1F, --SO.sub.2 --Ar.sub.F, --SO.sub.2 --R.sub.2 --Ar.sub.F ; --CO--R.sub.1F, --CO--R.sub.2 --R.sub.1F, --CO--Ar.sub.F, --CO--R.sub.2 -Ar.sub.F ; --R.sub.2 --NH--SO.sub.2 --R.sub.1F, --R.sub.2 --NH--SO.sub.2 --Ar.sub.F, --R.sub.2 --NH--SO.sub.2 --R.sub.2 --Ar.sub.F ; --R.sub.2 -SO.sub.2 --NH--R.sub.1F, --R.sub.2 -SO.sub.2 --NH--Ar.sub.F, --R.sub.2 --SO.sub.2 --NH--R.sub.2 --Ar.sub.F ; --R.sub.2 --NH--CO--R.sub.1F, --R.sub.2 --NH--CO--Ar.sub.F, --R.sub.2 --NH--CO--R.sub.2 --Ar.sub.F ; --R.sub.2 --CO--NH--R.sub.1F, --R.sub.2 --CO--NH--Ar.sub.F, --R.sub.2 --CO--NH--R.sub.2 --Ar.sub.F ; --R.sub.2 --S--R.sub.1F, --R.sub.2 --S--Ar.sub.F, --R.sub.2 --S--R.sub.2 --Ar.sub.F ; --R.sub.2 --O--R.sub.1F, --R.sub.2 -O-Ar.sub.F, --R.sub.2 -- O--R.sub.2 --Ar.sub.F ; --R.sub.2 --NH--R.sub.1F, --R.sub.2 --NH--R.sub.2 --Ar.sub.F ; --R.sub.2 --N(R.sub.3)--R.sub.1F, --R.sub.2 --N(R.sub.3)--R.sub.2 --Ar.sub.F ; --R.sub.2 --N(X)R.sub.1F, --R.sub.2 --N(X)--R.sub.2 --Ar.sub.F ; --R.sub.2 --N(R.sub.1F)--R.sub.2 --Ar.sub.F, and --R.sub.2 --N(R.sub.2 --Ar.sub.F).sub.2, PA1 --R.sub.1F : a straight chain or branched chain alkyl group which is substituted with one or more fluorine atoms and may contain X PA1 --R2--: a saturated or unsaturated hydrocarbon chain PA1 --R3: a lower alkyl group PA1 --.PHI.--: a phenylene group PA1 --Ar.sub.F : a group represented by following the formula ##STR3## (p represents an integer from 1 to 5, and q represents 0 or an integer from 1 to 4).
As described above, .sup.19 F-MRI has characteristics entirely different from those of the conventional .sup.1 H-MRI and can obtain new information useful in diagnoses. The MRI using .sup.19 F therefore has an extremely high utility value.
For example, when a fluorine compound having compatibility with blood is used as a contrast medium, a portion where a blood flow is present can be selectively imaged. This selective imaging of a blood flow is applicable to identification of an ischemia portion or a necrosis tissue. In addition, selective imaging of a particular tissue is possible when a substance which specifically recognizes a particular organ, a particular lesion, or a particular receptor is labeled with fluorine and used as a contrast medium.
Researches for applying the MRI diagnosis using .sup.19 F as a detectable nucleus to clinical examinations on the basis of the above potential utility value have already been reported or disclosed. Some of these researches are exemplified below.
In addition to the above examples, a large number of attempts to clinically apply the MRI diagnosis using .sup.19 F as a detectable nucleus have been reported. However, the .sup.19 F-MRI has not spread in clinical diagnoses yet. The primary cause for this is assumed to be the insufficient detection sensitivity of a fluorine compound administered as a contrast medium.
That is, since the detection sensitivity of a contrast medium is insufficient, a high-magnetic-field MRI apparatus which has not been clinically used must be employed in order to obtain enough information for diagnoses. An extremely long imaging time, on the other hand, is required in attempting to obtain enough information by using a clinical MRI apparatus that is normally used instead of the high-magnetic-field MRI apparatus. These situations prevent a wide spread of the .sup.19 F-MRI in clinical examinations.
The use of a large quantity of a fluorine compound may increase the imaging sensitivity. In this case, however, the toxicity of that fluorine compound poses a problem. As an example, in the blood vessel imaging experiment (report example (a) described above) using perfluorocarbon as a contrast medium, it is reported that a large amount of the contrast medium is necessary to obtain high-quality images. An application of such the imaging method to human bodies accompanies a serious problem in respect of toxicity.
In addition, when tissue specific imaging is performed by using, as a contrast medium, a substance which has a specific tissue affinity (e.g., a monoclonal antibody; to be referred as a tissue specific substance hereinafter) modified with fluorine, the contrast with respect to the background is impaired by the use of a large amount of the contrast medium. On the other hand, it is practically impossible to improve the detection sensitivity by modifying this tissue specific substance with a large number of fluorine atoms for the reasons to be explained below. First, it is very difficult in view of the synthesis reaction to perform modification of the substance with such a large number of fluorine atoms. Second, even if the modification is possible, this modification with such a large number of fluorine atoms degrades the tissue specificity of the tissue specific substance and also leads to an increase in toxicity.